Intermediate products, methods for their preparation and use thereof

ABSTRACT

Novel solid supported intermediate products of the general formula  
                 
 
     coupled to a solid polymeric support through one or both of the R 1  groups or through the R 4  group which are suitable for synthesis of heterocyclic compounds are disclosed. Methods for preparing such intermediate products are also disclosed and also the use of the intermediate products in simple and fast methods on solid phase for synthesis of heterocycles.

FIELD OF THE INVENTION

[0001] The present invention relates to novel solid supportedintermediate products suitable for synthesis of heterocyclic compoundsand methods for preparing such intermediate products. The invention alsorelates to use of the intermediate products in simple and fast methodson solid phase for synthesis of heterocycles with large structuraldiversity in high yields and high purity.

BACKGROUND OF THE INVENTION

[0002] Highly functionalized heterocycles of various ring sizes, withdifferent heteroatoms and substitution patterns are of major interest inthe pharmaceutical and agricultural industry due to the many intrinsicbiological properties of these substances.

[0003] In medicinal chemistry in general, and combinatorial chemistry inparticular, the use of versatile synthons or versatile scaffolds, whichare available after only a few reaction steps, are of great interest. Anexample of a reagent producing such synthons is N,N-dimethylformamidediethyl acetal (DMFDEA), cf. Abdulla, R. F.; Brinkmeyer, R. V.,Tetrahedron, 1979, 35, 1675-1735. Condensation reactions between anactivated methyl or methylene group adjacent to an ester or ketofunctionality and DMFDEA form dimethylaminopropenoates(A) ordimethylaminopropenones (B), see FIG. 1.

[0004] These intermediates, in which the dimethylamino moiety acts as agood leaving group, have been used in reactions in solution underconventional heating methods which has been described for example inStanovnik, B.; Svete, J., Synlett, 2000, 8, 1077-1091. The intermediatescould then be reacted with dinucleophiles to form differentheterocycles. The availability of starting materials, which could formactivated alkylaminopropenones or alkylaminopropenoates with DMFDEA islarge and the number of possible heterocycles with large diversity,which are possible to form in a subsequential step from these types ofintermediates is substantial. The formation of heterocycles from theseintermediates takes place via a cascade or domino-type reaction, cf.Tietze, L. F., Chem.Rev.,1996,115-136, which means that it involves twoor more new bond formations taking place under the same reactionconditions. The advantages of this kind of reaction as compared totraditional multi-step reactions are simplified engineering, nointermediate work-up, minimized waste handling and lower cost ofpurification. All of these are important factors to consider whenworking the synthesis of combinatorial libraries.

[0005] Microwave heating has been used in organic synthesis since 1986,cf. Gedye, R.; Smith, F.; Westaway, K.; Ali, H.; Baldisera, L.; Laberge,L.; Rousell, J., Tetrahedron Lett. 1986, 27, 279-282. Microwave heatingreduces the reaction times in comparison with traditional heating. Inaddition, the yields of the reactions are often increased and the timefor optimizing the reaction conditions is minimized in comparison toconventional heating methods.

SUMMARY OF THE INVENTION

[0006] The present invention relates in one aspect to new intermediateproducts of the general formula I suitable for synthesis of heterocycliccompounds.

[0007] In another aspect the present invention relates to methods forpreparing intermediates of formula I.

[0008] According to another aspect the invention relates to the use ofan intermediate product of the general formula I for synthesis ofheterocyclic compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009]FIG. 1 shows condensation reactions between an activated methyl ormethylene group adjacent to an ester or keto functionality and DMFDEAform dimethylaminopropenoates(A) or dimethylaminopropenones (B)

[0010]FIG. 2 shows examples of heterocyclic compounds prepared byreaction of intermediate products according to the present invention,3-dimethylamino propenoates, with different dinucleophiles areillustrated.

[0011]FIG. 3 shows examples of heterocyclic compounds prepared byreaction of intermediate products according to the present invention,3-dimethylamino propenones, with different dinucleophiles areillustrated.

[0012]FIG. 4 shows an example of the formation of an intermediateproduct wherein the substrate is bound to the solid resin could becarried out in a two-step reaction.

[0013]FIG. 5 shows an example of a synthesis method for preparing solidphase bound dialkylamino propenones.

[0014]FIG. 6 shows examples of synthesis of heterocycles via solid phasebound dialkylamino propenoates.

[0015]FIG. 7 shows examples of synthesis of heterocycles via solid phasebound dialkylamino propenones.

DETAILED DESCRIPTION OF THE INVENTION

[0016] More closely the invention relates to an intermediate productsuitable for synthesis of heterocyclic compounds which intermediatecompound has the general formula I

[0017] coupled to a solid polymeric support through one or both of theR¹ group(s) or through the R⁴ group

[0018] wherein when coupled to the polymeric support through R¹

[0019] The R¹ groups represent the same or different groups chosen fromlower alkyl with 1 to 6 carbon atoms, such as methyl, ethyl, cycloalkylwith 3 to 6 carbon atoms in the ring, such as cyclopentyl, cyclohexyl,heterocyclic compounds including one or more heteroatoms, benzyl groups.Two R¹ groups together can be included in a heterocyclic ring containingone or more nitrogen atoms;

[0020] R² represents H or a lower alkyl with 1 to 6 carbon atoms, suchas methyl;

[0021] R⁴ represents unsubstituted or substituted aromatic ring(s),unsubstituted or substituted heteroaromatic ring(s) with one or moreheteroatoms, or OR⁵; when R⁴ is unsubstituted or substituted aromaticring(s), unsubstituted or substituted heteroaromatic ring(s), R³represents H, alkyl, unsubstituted or substituted aromatic ring,unsubstituted or substituted heteroaromatic ring with one or moreheteroatoms, or COOR⁵;

[0022] when R⁴ is OR⁵, R³ is CN, COOR⁵, NCOR⁵, NCOOR⁵, or COR⁵;

[0023] the R⁵ groups, which can be the same or different, represent H,alkyl, benzyl, unsubstituted or substituted aromatic ring(s),unsubstituted or substituted heteroaromatic ring(s) with one or moreheteroatoms;

[0024] and wherein when coupled to the polymeric support through R⁴

[0025] R¹ and R² are as defined above,

[0026] R³ is as defined above except COOR⁵ and COR⁵,

[0027] R⁴=OR⁵ where R⁵ is as defined above except H.

[0028] When producing a large number of substances in solution thesubsequent purifications will be time-consuming. However, it hasaccording to the present invention been found that solid phasetechnique, which allows for easy automation together with microwaveassisted heating, gives rise to unexpected advantages such as highyields of the heterocyclic compounds with high purity and possibility toeliminate time-consuming purification steps, which are necessary whenproducing heterocyclic compounds in solution according to the abovementioned prior art. Furthermore, in the method according to the presentinvention a large excess of reagent could be used in a reaction with aresin bound substrate whereby the reaction is driven to completion. Theredundant amount of reagent could then be removed by a simplefiltration. Furthermore, by the use of microwave heating in solid phasesynthesis in accordance with the present invention the reaction times inthe heterogeneous systems can be substantially shortened as compared toother methods of heating.

[0029] The intermediate products according to the present invention aresuitable to use for preparing heterocyclic compounds by reaction withdinucleophiles and in FIG. 2 examples of heterocyclic compounds preparedby reaction of intermediate products according to the present invention,3-dimethylamino propenoates, with different dinucleophiles areillustrated.

[0030] In FIG. 3 examples of heterocyclic compounds prepared by reactionof intermediate products according to the present invention,3-dimethylamino propenones, with different dinucleophiles areillustrated.

[0031] The solid polymeric support to which the compounds are coupledcould be the following: a.) beads, pellets, disks, fibers, gels, orparticles such as cellulose beads, pre-glass beads, silica gels,polypropylene beads, polyacrylamide beads, polystyrene beads that arelightly cross-linked with 1-2% divinylbenzene and optionally graftedwith polyethylene glycol and optionally functionalized with amino,hydroxy, carboxy or halo groups; and b.) soluble supports such as lowmolecular weight non-cross-linked polystyrene and polyethylene glycol.The term solid support is used interchangeably with the term resin orbead in this invention and is intended to mean the same thing. Forpropenoates any resin which can form an alkyl or benzylic ester from acarboxylic acid such as polystyrene-divinylbenzene resins eg. Merrifieldresin (benzyl chloride handle), Wang resin (benzyl alcohol handle),Tentagel PHB (benzyl alcohol handle), Resin with PAM anchor, Rink resin,PEGA resin are examples of suitable resins. For propenones any resinwith a dialkyl amine handle, any resin which can form a dialkyl amine orbenzyl alkyl amine handle such as Merrifield resin (displacement of achloride with an alkylamine), Rink resin (methylation of a primary aminewith methyliodide), amino methyl resin, trisamine resin, SASR¹N resin,Behring resin, PAM resin, N-methylaminomethyl resin HCl are examples ofsuitable resins for use as solid support.

[0032] In the methods for preparing the intermediates according to thepresent invention N-disubstituted carboxamide acetals of the generalformula II are suitable to use as a reactant

[0033] wherein the two R⁷ groups are the same or different groupsselected from alkyl groups with 1 to 6 carbon atoms, cycloalkyl groupswith 3 to 6 carbon atoms, benzyl groups, cyclic compounds includingheterocyclic compounds with one or more heteroatoms, R⁷ is suitablymethyl, ethyl. The two R⁷ groups could together be part of a carbocyclicor heterocyclic ring, for example imidazole.

[0034] The two R⁸ groups are the same or different groups selected fromstraight, branched or cyclic alkyl chains, substituted such alkylchains, benzyl groups. R⁸ is suitably Me, Et. The two R⁸ groups couldtogether be part of a carbocyclic ring for example 1,3 dioxane.

[0035] In a method of preparing an intermediate of formula I, which iscoupled to the solid polymeric support through one or both R¹ groups(propenones) a polymeric support with a reactive secondary amine isprepared according to the following reaction whereby a product offormula IV is obtained

[0036] wherein Y is a spacer group which can be alky, benzyl, trityl or[OCH₂CH₂]n, R¹ is as defined in claim 1, X is NH₂, halogen or triflate.When X is NH₂ A is halogen or triflate, and when X is halogen ortriflate, A is NH₂,

[0037] which product of formula IV then is reacted with a N-substitutedcarboxamide acetal of the general formula II as defined above

[0038] and a substance with a methylene or methyl group adjacent to aketo function according to the general formula III

[0039] where R³, R⁴ are as defined in claim 1, whereby a compound offormula I coupled to the polymeric support through one or both of the R¹groups is obtained.

[0040] In another method of preparing an intermediate of formula I,which is coupled to the solid polymeric support through one or both ofthe R¹ groups (propenones), a polymeric support with a reactivesecondary amine is prepared according to the following reaction, wherebya product of formula V is obtained

[0041] wherein Y is as defined above, R¹⁰ is a secondary amine, B and Dare functional groups which form a covalent bond when reacted with eachother, and when n=0, B is a leaving group, which product of formula Vthen is reacted with a N-disubstituted carboxamide acetal of the generalformula II as defined above

[0042] and a substance with a methylene or methyl group adjacent to aketo function according to the general formula III as defined above,whereby a compound of formula I coupled to the polymeric support throughone or both of the R¹ groups is obtained.

[0043] In a method of preparing an intermediate of formula I, which iscoupled to the solid polymeric support through the R⁴ group(propenoates) a polymeric support of the general formula VI

[0044] with a reactive X end group, wherein X and Y are as defined inclaim 2, is reacted with a compound of the general formula VII

[0045] wherein R³ is defined as in claim 1 and R⁹ is H, alkyl, benzyl orphenyl, whereby a product of the formula VIII

[0046] is obtained, which product of formula VIII then is reacted with aN-disubstituted carboxamide acetal of the general formula II as definedabove, whereby a compound of formula I is obtained which is coupled tothe solid polymeric support through the R⁴ group.

[0047] In the above methods for preparing the intermediates according tothe present invention it is suitable to carry out the reactions by meansof heating. The heating is suitably induced by the use of microwaves.The temperature is generally between 100 and 250° C. It is oftensuitable to carry out the reactions in a closed vessel.

[0048] The intermediate products according to the present invention areuseful for the synthesis of heterocyclic compounds wherein a solidsupported intermediate compound of the general formula I is reacted witha dinucleophile, i.e. a substance with two nucleophilic atoms selectedfrom N, C, O and S adjacent to each other or separated by one or morecarbon atoms, by heating the intermediate compound and thedinucleophilic substance in a solution for a short period of time which,after evaporation of the solvent, produces the desired heterocycliccompound in high yield and high purity.

[0049] The heating is suitably induced by the use of microwaves and auseful temperature is between 100 and 250° C. The reaction time neededis short and suitably less than 30 minutes.

[0050] Dialkylamino propenoates coupled to a solid support react withdinucleophiles in a two-step reaction wherein substitution of thedialkylamino group is followed by a nucleophilic attack on the esterfunctionality, which cleaves the ester.

[0051] Dialkylamino propenones coupled to a solid support react in asomewhat different manner with dinucleophiles. A condensation reactionwith the keto function is followed by the substitution of thedialkylamino group.

[0052] Heterocycle formation from dialkylamino propenones anddialkylamino propenoates. The intermediates could be reacted with manydinucleophiles such as hydrazines, amidines, diketo substrates and2-amino-pyridines to form heterocyclic compounds such as isoxazoles,pyrazoles, chromones, pyrimidines, pyranones, pyrimidones, pyranones,pyrimidones and substituted 4H-quinolizin-4-ones all of which have greatinterest as potential druglike compounds. Many of the mentioned productshave in the literature been described to induce biological activity.

[0053] Dinucleophiles are defined as any substances with twonucleophilic atoms adjacent to each other or separated by one or morecarbon atoms. The nucleophilic atoms are chosen from N, C, O, S.Examples of suitable dinucleophiles are hydroxylamine, hydrazine,substituted hydrazines, substituted amidines, 2-aminopyridines,2-pyridino acetonitrile, 2-aminopyrazoline, 2-aminopyridazine,substituted 1,3-diketohexane and cyclohexane, 2-aminothiazole and3-amino-2-pyraxolin-5-ones. Examples of some dinucleophiles areillustrated below.

[0054] Synthesis of Solid Phase Bound Dialkylamino Propenoates

[0055] Formation of an intermediate product wherein the substrate isbound to the solid resin could be carried out in a two-step reaction, anexample of which is shown in FIG. 4.

[0056]FIG. 4 shows the reaction between a solid support, Merrifieldresin, and hippuric acid (1) in the first step and reaction of theproduct formed (2) with DMFDEA (3) which gives the intermediate product(4). Magic angle spinning NMR (MAS-NMR) analysis (Wehler, T.; Westman,J. Tetrahedron Lett. 1996, 37, 4771-4774) was used for the protocoldevelopment. An ester linkage was formed between the carboxylic acidsubstrate and the solid phase resin in step one. By comparing the peakarea from the methylene group in the resin handle (PhCH₂Cl) and the peakarea from the solid phase benzylester methylene group (PhCH₂OCO) theyield could be determined. In this example the Merrifield resin wastreated with the N-acylated glycine derivative (hippuric acid) togetherwith cesium carbonate in DMF under microwave heating at 200° C. for 10minutes. MAS-NMR analysis and elemental analysis showed a loading ofapproximately 1 mmol/g (80% yield), which is in the same range asdescribed in the literature but in approximately a 100-fold shorterreaction time. Merrifield resin was suitable to use due to the highloading capacity and high thermal stability. After washing the resin wasmixed with 5 eq. DMFDEA in 2.5 ml DMF and exposed to microwaves at 180°C. for 10 minutes to form the dimethylamino propenoate intermediateproduct 4 according to the invention.

[0057] Synthesis of Solid Phase Bound Dialkylamino Propenones

[0058] An example of a synthesis method for preparing solid phase bounddialkylamino propenones is illustrated in FIG. 5.

[0059] In the first step in this synthesis Merrifield resin was treatedwith methyl amine in water under microwave heating at 150° C. for 10minutes to form a benzyl methyl amine on the solid resin (13). Afterwashing the resin was treated with 5 eq. DMFDEA together with 5 eq.4-phenoxyacetophenone under microwave heating at 180° C. for 10 minutesin DMF to form the intermediate product [14), the solid supported benzylmethyl aminopropenone according to the present invention in athree-component reaction.

[0060] The intermediate products according to the present invention werethen used for the synthesis of heterocycles by reacting the solidsupported intermediates with dinucleophiles in a suitable solvent e.g.at 180° C. for 10 min.

[0061] In FIG. 6 examples of synthesis of heterocycles via solid phasebound dialkylamino propenoates are illustrated.

[0062] In FIG. 7 examples of synthesis of heterocycles via solid phasebound dialkylamino propenones are illustrated.

[0063] The invention is illustrated by means of the following examples,which are presented only for illustrative purpose and are not meant tolimit the scope of the invention in any way.

EXAMPLES

[0064] The microwave-assisted reactions were performed in a single modemicrowave cavity, an instrument from Personal Chemistry. NMR spectrawere recorded in CDCl₃ or DMSO-d₆ at 25° C., using a Bruker at 300 MHz(¹H)/75 MHz (¹³C) or a Varian 600 MHz instrument with a Nano probe forthe MAS-NMR analysis. All NMR spectra recorded were in agreement withthe postulated structures and only selected data are reported. Elementalanalyses were performed by Mikrokemi AB, Uppsala, Sweden. All startingreagents were of the best grade available (Aldrich or Lancaster) andwere used without purification. The reactions were run in a closedvessel and that in several cases the pressure during the reaction wasbetween 5-20 bar.

[0065] Coupling of N-benzoyl glycine to Merrifield resin (2). 200 mgMerrifield resin (1.25 mmol/g loading capacity) was swelled in 2.5 mLDMF, 1.25 mmol (5 equiv.) N-benzoyl glycine (Hippuric acid) (1) and 1.25mmol Cs₂CO₃ were added and the reaction mixture was heated at 200° C.for 10 min. The reaction mixture was then cooled down to roomtemperature by pressurized air. The residue was then washed severaltimes with DMF, water and DCM. The resin was dried under reducedpressure in a desiccator. MAS-NMR analysis indicated compound 2 in ayield of 80% (approx. 1.0 mmol/g loading). 1H NMR (CDCl3): δ 4.24(COCH₂NCO), 5.11 (PhCH₂CO), 7.3-7.4 (4H, aromatic), 7.8 (1H, aromatic).Elemental analysis: 1.35 weight percent giving 0.96 mmol/g loading.

[0066] Methylamination f Merrifield resin (13). 200 mg Merrifield resin(1.25 mmol/g loading capacity) was treated with 2.0 mL methylamine inwater (40% w/w) (excess) at 150° C. for 5 min. The reaction mixture wasthen cooled to room temperature by pressurized air. The residue waswashed several times with Water, DCM and MeOH to give compound 13.Elemental analysis gave 1.52 weight percent giving approx. 1.08 mmol/gloading.

[0067] Dimethyl amino propenoates from N-benzoyl glycine on solidsupport (4). 250 mg of solid supported N-benzoyl glycine benzyl ester 2(approximately 0.25 mmol) was swelled in 2.5 mL DMF, 1.57 mmol DMFDEAwas added and the reaction mixture was heated at 180° C. for 10 min. Thereaction mixture was then cooled to room temperature by pressurized air.The residue was washed several times with DMF, water and DCM. The resinwas dried under reduced pressure in a desiccator. MAS-NMR analysisindicate compound 4 but no yield was determined due to low resolution.

[0068] Benzyl methyl amino propenones from 4-phenoxy acetophenone onsolid support (14). 200 mg of benzyl methylamine on solid support 13(approximately 0.2 mmol) was swelled in 2.0 mL DMF, 214 μL DMFDEA and155 μL 4-phenoxy acetophenone were added and the reaction mixture washeated at 180° C. for 10 min. The reaction mixture was then cooled downto room temperature by pressurized air. The residue was washed severaltimes with DMF, water and DCM. The resin was dried under reducedpressure in a desiccator. MAS-NMR analysis indicated compound 14 but noyield was determined due to low resolution.

[0069] Benzyl methyl amino propenones from ethyl 4-nitrobenzoylacetateon solid support (19). 200 mg of Benzyl methylamine on solid support 13was treated with ethyl 4-nitrobenzoylacetate as described above for thesynthesis of compound 19. MAS-NMR analysis indicated compound 19 but noyield was determined due to low resolution.

[0070] 3-(benzoyl)amino-4H-pyrido[1,2-a]pyrimidin-4-ne (6.) 100 mg ofthe solid supported compound 4 were added to 6.6 mg 2-aminopyridine (5)(0.07 mmol) in 0.5 mL of acetic acid. The solution was exposed tomicrowaves at 180° C. for 10 minutes and then cooled to roomtemperature. The acetic acid was evaporated giving 14.2 mg of product 6,a total yield of 77% and 96% purity based on LC/MS analysis. Thestructure was confirmed by ¹H NMR (300 MHz, CDCl₃): δ 7.16 (dt, 1H,ArH), 7.45-7.65 (m, 4H, ArH), 7,75 (dd, 1H, ArH), 7.95 (dd, 2H, ArH),8.84 (s, 1H, NH), 8.95 (dd, 1H, ArH), 9.75 (s, 1H, pyrimidin-H).

[0071] 3-(benzoyl)amino-1-cyano4H-quinolizin-4-one (17). 100 mg of thesolid supported compound 4 were added to 5.6 μL 2-pyridyl-acetonitrile(15) (0.05 mmol) in 0.5 mL of acetic acid. The solution was exposed tomicrowaves at 180° C. for 10 minutes and then cooled to roomtemperature. The acetic acid was evaporated. The residue was dissolvedin DCM and filtered through a plug of silica. Crude analysis showed aLC/MS purity of 94%. Evaporation of the solvent gave the product 17 in13.3 mg, a total yield of 92%. The structure was confirmed by ¹H NMR(300 MHz, CDCl₃): δ NMR 7.02 (ddd, 1H, ArH), 7.32-7.42 (m, 4H, PhH),7.77 (m, 2H, ArH), 7.81 (dt, 1H, ArH), 8.88 (s, 1H, NH), 8.92 (dt, 1H,ArH), 9.11 (s, 1H, quinolizin-4-one).

[0072] 3-(benzoyl)amino-5-oxo-5,6,7,8-tetrahydro-2H-1-benzopyran-2-one(18). 100 mg of the solid supported compound 4 were added to 7.0 mg 5,5dimethyl-1,3-cyclohexanedione (16) in 0.5 mL of acetic acid. Thesolution was exposed to microwaves at 180° C. for 10 min. and thencooled to room temperature. The acetic acid was evaporated giving 14.8mg of product 18, a total yield of 95% and 98% purity based on LC/MSanalysis. The structure was confirmed by ¹H NMR (300 MHz, CDCl₃): δ 1.2(s, 6H, CH₃) 2.48 (s, 2H, CH₂), 2.78 (s, 2H, CH₂), 7.5-7.7 (m, 3H, ArH),7.92 (m, 2H, ArH), 8.59 (s, 1H, NH), 8.83 (s, 1H, CH).

[0073] (4-phenoxy)phenylisoxazole (23). 200 mg of the solid supportedcompound 14 was mixed with 0.1 (0.5 equiv.) mmol of hydroxylaminehydrochloride (20) and 2 mL of EtOH. The mixture was exposed tomicrowaves at 180° C. for 10 minutes and then cooled to roomtemperature. The solvent was evaporated. The product 23 was isolated in81% yield and 87% purity based on LC/MS analysis and characterized by ¹HNMR (300 MHz, CDCl₃): δ 6.44 (d, 1H, J=1.9 Hz, isoxazole), 7.04 (m, 4H,ArH), 7.17 (dt, 1H, ArH), 7.38 (m, 2H, ArH), 7.76 (m, 2H, ArH), 8.25 (d,1H, J=1.9 Hz, isoxazole).

[0074] 1-phenyl-5-(4-phenoxyphenyl)-pyrazole (24). 200 mg of the solidsupported compound 14 was mixed with 0.1 (0.5 equiv.) mmol ofphenylhydrazine (21) and 2 mL of acetic acid. The mixture was exposed tomicrowaves at 180° C. for 10 minutes and then cooled to roomtemperature. The solvent was evaporated. The product 24 was isolated in81% yield and 93% purity and characterized by ¹H NMR (300 MHz, CDCl₃): δ6.48 (d, 1H, J=1.9 Hz, pyrazole), 6.91 (dd, 2H, ArH), 7.03 (m, 2H, ArH),7.18 (dd, 2H, ArH), 7.3-7.4 (m, 8H, ArH), 7.71 (d, 1H, J=1.9 Hz,pyrazole).

[0075] Ethyl (1-phenyl-3-(4-nitro)-phenyl pyrazole-4-carboxylate (25).200 mg of the solid supported compound 19 were treated as described forcompound 24 using EtOH as solvent. The EtOH was evaporated giving 31.0mg of product 25 in 92% yield and 91% purity. The structure wasconfirmed by ¹H NMR (300 MHz, CDCl₃): δ 1.28 (t, 3H, CH₃CH₂), 4.25 (q,2H, CH₂CH₃), 7.20 (m, 2H, ArH), 7.35 (m, 3H, ArH), 7.51 (d, 2H, ArH),8.21 (d, 2H, ArH), 8.23 (s, 1H, pyrazole).

[0076] Ethyl 2-(4-pyridyl)-4-(4-nitrophenyl)-pyrimidine-5-carboxylate(26). 200 mg of the solid supported compound 19 in 2 mL DMF was treatedwith 0.1 mmol (approx. 0.5 equiv.) 4-amidinopyridine hydrochloride (22)and 0.15 mmol KOH, exposed to microwaves at 180° C. for 10 minutes andthen cooled to room temperature. The solvent was evaporated. The product(26) was isolated in 94% (32.7 mg) in 91% purity. The structure wascharacterized by ¹H NMR (300 MHz, CDCl₃): δ 1.22 (t, 3H, CH₃CH₂), 4.28(q, 2H, CH₂CH₃), 7.54 (m, 3H, PhH), 7.85 (m, 2H, PhH), 8.35 (dd, 2H,pyridyl), 8.56 (dd, 2H, pyridyl), 9.31 (s, 1H, pyrimidine).

[0077] According to the present invention activated aminopropenoates andaminopropenones on solid phase are provided which intermediate productscan be used in combinatorial syntheses of a large number of differentheterocycles with an overall reaction time of approximately 30 minutesto give the products in high purity in high to excellent yields. Onemajor benefit obtained by this approach is that purification is notneeded.

1. An intermediate product suitable for synthesis of heterocycliccompounds which is a compound of the general formula I

coupled to a solid polymeric support through one or both of the R¹groups or through the R⁴ group wherein when coupled to the polymericsupport through R¹ the R¹ groups represent the same or different groupschosen from lower alkyl with 1 to 6 carbon atoms, such as methyl, ethyl,cycloalkyl with 3 to 6 carbon atoms in the ring, such as cyclopentyl,cyclohexyl, heterocyclic compounds including one or more heteroatoms,benzyl groups; two R¹ groups together can be included in heterocyclicring containing one or more nitrogen atoms; R² represents H or a loweralkyl with 1 to 6 carbon atoms, such as methyl; R⁴ representsunsubstituted or substituted aromatic ring(s), unsubstituted orsubstituted heteroaromatic ring(s) with one or more heteroatoms, or OR⁵;when R⁴ is unsubstituted or substituted aromatic ring(s), unsubstitutedor substituted heteroaromatic ring(s), R³ represents H, alkyl,unsubstituted or substituted aromatic ring, unsubstituted or substitutedheteroaromatic ring with one or more heteroatoms, or COOR⁵; when R⁴ isOR⁵, R³ is CN, COOR⁵, NCOR⁵, NCOOR⁵ or COR⁵; the R⁵ groups, which can bethe same or different, represent H, alkyl, benzyl, unsubstituted orsubstituted aromatic ring(s), unsubstituted or substitutedheteroaromatic ring(s) with one or more heteroatoms; and wherein whencoupled to the polymeric support through R⁴ R¹ and R² are as definedabove, R³ is as defined above except COOR⁵ and COR⁵ R⁴=OR⁵ where R⁵ isas defined above except H.
 2. A method of preparing an intermediate offormula I according to claim 1, which is coupled to the solid polymericsupport through one or both R¹ groups (propenones), wherein a polymericsupport with a reactive secondary amine, is prepared according to thefollowing reaction whereby a product of formula IV is obtained

wherein Y is a spacer group which can be alkyl, benzyl, trityl or[OCH2CH2]_(n), R¹ is as defined in claim 1, X is NH₂, halogen ortriflate; when X is NH₂, A is halogen or triflate, and when X is halogenor triflate, A is NH₂, which product of formula IV then is reacted witha N-disubstituted carboxamide acetal of the general formula II

wherein the R⁷ groups are different or the same chosen from C1-C6 alkyl,cycloalkyl with 3 to 6 carbon atoms , benzyl groups, cyclic compoundsincluding heteroatoms, the two R⁷ groups could together be part of acarbocyclic or heterocyclic ring, the R⁸ groups could be the same ordifferent chosen from straight, branched or cyclic alkyl chains, benzylgroups, and alkyl chains with substituents; the two R⁸ groups couldtogether be part of a carbocyclic ring and a substance with a methyleneor methyl group adjacent to a keto function according to the generalformula III

where R³, R⁴ are as defined in claim 1, whereby a compound of formula Icoupled to the polymeric support through one or both of the R¹ groups isobtained.
 3. A method of preparing an intermediate of formula Iaccording to claim 1, which is coupled to the solid polymeric supportthrough one or both R¹ groups (propenones), wherein a polymeric supportwith a reactive secondary amine is prepared according to the followingreaction whereby a product of formula V is obtained

wherein Y is as defined in claim 2, R¹⁰ is a secondary amine, B and Dare functional groups which form a covalent bond when reacted with eachother, and when n=0 B is a leaving group, which product of formula Vthen is reacted with a N-disubstituted carboxamide acetal of the generalformula II

wherein R⁷ and R⁸ are defined as in claim 2, and a substance with amethylene or methyl group adjacent to a keto function according to thegeneral formula III

where R³, R⁴ are as defined in claim 1 whereby a compound of formula Icoupled to the polymeric support through one or both of the R¹ groups isobtained.
 4. A method of preparing an intermediate of formula Iaccording to claim 1 which is coupled to the solid polymeric supportthrough the R⁴ group (propenoates), wherein a polymeric support of thegeneral formula VI

with a reactive X end group, wherein X and Y are as defined in claim 2is reacted with a compound of the general formula VII

wherein R³ is as defined in claim 1 and R⁹ is H, alkyl, benzyl orphenyl, whereby a product of the formula VIII

is obtained, which product of formula VIII then is reacted with aN-disubstituted carboxamide acetal of the general formula II

wherein R⁷ and R⁸ are defined as in claim 2, whereby a compound offormula I is obtained which is coupled to the solid polymeric supportthrough the R⁴ group.
 5. Use of an intermediate product for synthesis ofheterocyclic compounds which is a compound of the general formula I

coupled to a solid polymeric support through one or both of the R¹groups or through the R⁴ group, wherein when coupled to the polymericsupport through R¹, the R¹ groups represent the same or different groupschosen from lower alkyl with 1 to 6 carbon atoms, such as methyl, ethyl,cycloalkyl with 3 to 6 carbon atoms in the ring, such as cyclopentyl,cyclohexyl, heterocyclic compounds including one or more heteroatoms,benzyl groups; two R¹ groups together can be included in a heterocyclicring containing one or more nitrogen atoms; R² represents H or a loweralkyl with 1 to 6 carbon atoms, such as methyl; R⁴ representsunsubstituted or substituted aromatic ring(s), unsubstituted orsubstituted heteroaromatic ring(s) with one or more heteroatoms or OR⁵;when R⁴ is unsubstituted or substituted aromatic ring(s), unsubstitutedor substituted heteroaromatic ring(s), R³ represents H, alkyl,unsubstituted or substituted aromatic ring, unsubstituted or substitutedheteroaromatic ring with one or more heteroatoms or COOR⁵; when R⁴ isOR⁵, R³ is CN, COOR⁵, NCOR⁵, NCOOR⁵ or COR⁵; the R⁵ groups, which can bethe same or different, represent H, alkyl, benzyl, unsubstituted orsubstituted aromatic ring(s), unsubstituted or substitutedheteroaromatic ring(s) with one or more heteroatoms; and wherein whencoupled to the polymeric support through R⁴ R¹ and R² are as definedabove, R³ is as defined above except COOR⁵ and COR⁵, R⁴=OR⁵ where R⁵ isas defined above except H, wherein the solid supported intermediatecompound of the general formula I is reacted with a dinucleophile, i.e.a substance with two nucleophilic atoms selected from N, C, O and Sadjacent to each other or separated by one or more carbon atoms, byreacting the intermediate compound and the dinucleophilic substance fora short period of time which after evaporation of the solvent producesthe desired heterocyclic compound in high yield and in high purity.
 6. Amethod according to any of claims 2-4 wherein the reactions areperformed under heating.
 7. A method according to claim 6 wherein theheating is induced by the use of microwaves.
 8. A method according toany of claims 2-4 and 6-7 where the solid polymeric support to which thecompounds are coupled is polystyrene beads that are lightly cross-linkedwith 1-2% divinylbenzene and optionally grafted with polyethyleneglycol.
 9. A method according to claims 2 and 8 where the solidpolymeric support is polystyrene beads which are functionalized withhalogen and triflate or NH₂.
 10. A method according to claims 3 and 8where the polystyrene beads are functionalized with B as defined informula V.
 11. A method according to claims 4 and 8 where thepolystyrene beads are functionalized with halogen or hydroxyl.
 12. Amethod according to claim 2 or 3 where the substance with a methylene ormethyl group adjacent to a keto function according to the generalformula III is a substituted acetophenone or a beta ketoester.
 13. Amethod according to claim 4 where the substance according to the generalformula III is a N-substituted glycine ester or a substituted aceticacid ester.
 14. A method according to any of claims 2-12 wherein thedisubstituted carboxamide acetal of formula II is dimethylformamidediacetal.